Response to letter by Dr. M. S. A. Mohamed (Antagonizing reactive oxygen species during lung perfusion).
Response to letter by Dr. M. S. A. Mohamed (Antagonizing reactive oxygen species during lung perfusion).
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对 M. S. A. Mohamed 博士的信件的回应（在肺灌注过程中拮抗活性氧）。
DOI：
10.1152/ajplung.00310.2014
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Fisher,AronB
中科院分区：
文献类型：
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作者：
Chatterjee,Shampa;Nieman,GaryF;Christie,JasonD;Fisher,AronB
致编辑：我们感谢MSA Mohamed博士对我们最近关于内皮机械信号及其在肺移植中的意义的论文的深刻评论（1）。我们很高兴，正如我们的文章所强调的，作者同意使用KATP通道激动剂将是减少肺储存期间氧化损伤的良好策略。我们建议在（肺）移植物保存溶液中使用KATP激动剂（在这种情况下为cromakalim），这是基于我们的信号传导研究，该研究表明，由于该通道关闭导致的去极化驱动了缺血时活性氧（ROS）的产生（2，3，6）。穆罕默德博士提出了另一种可能性。他提出了肺移植的缺血再灌注（I/R）类似于缺血预处理或IPC，已被广泛报道在几个器官中具有保护作用。IPC提供的保护部分来自KATP通道的激活。因此，基于IPC模型，使用KATP激动剂将是减少氧化损伤的明显选择。但是，尽管IPC或多次短暂缺血（1-3分钟）后再灌注的保护作用在中枢神经和心脏系统中是已知的，但与IPC对肺的作用相关的数据相对有限。除了肺的储存和标准EVLP（离体肺灌注）技术本身不模拟IPC操作（缺血时间相当长并且在1-6小时之间的范围内，并且再灌注也持续更长的时间）。然而，正如作者所建议的，短时间的缺血，在它们之间有一段时间的EVLP灌注，可能会减少氧化损伤。肺I/R的IPC效应通常是通过其他远端器官缺血（如后肢或心脏）的全身预处理实现的（4，5）。因此，需要进一步研究IPC在肺I/R和EVLP操作中的作用。正如Mohamed博士所建议的那样，通过向肺保存溶液中添加抗氧化剂来拮抗ROS（通过阻断氧化损伤和炎症级联反应）将是一种合理的保护策略。因此，EVLP的氢气疗法可能由于其抗氧化作用而有希望，但迄今为止尚未完全评估。或者，抑制导致肺I/R产生ROS的级联反应，而不是在产生ROS后清除ROS，可能是一种更好的方法。这部分是因为保护性抗氧化剂治疗迄今为止具有混合的临床反应，并且因为理论上ROS清除剂难以与组织组分竞争与ROS反应。当然，这并不表明单独或与KATP激动剂组合添加抗氧化剂到肺灌注液或储存溶液中将没有额外的保护作用。移植后的信号传导代表了几个事件的合并。除了I/R，免疫、炎症和伴随的先天免疫应答也在氧化损伤和移植物功能障碍的发病机制中起作用。了解这些途径以及它们如何交叉可以帮助确定可以减弱驱动这种发病机制的信号事件的药物。在这个方向上，我们的文章强调了我们对肺内皮细胞“机械信号”级联反应的理解如何转化为在肺移植物保存溶液中加入药物。
TO THE EDITOR: We thank Dr. MSA Mohamed for his insightful comments regarding our recent paper on endothelial mechanosignaling and its implications in lung transplant (1). We are glad that, as emphasized by our article, the author agrees that the use of KATP channel agonist (s) would be a good strategy to reduce oxidative damage during storage of lungs. Our suggested use of a KATP agonist (in this case cromakalim) in the (lung) graft preservation solution is based on our signaling studies showing that depolarization resulting from closure of this channel drives reactive oxygen species (ROS) production with ischemia (2, 3, 6). Dr. Mohamed suggests another possibility. He raises the point that ischemia reperfusion (I/R) with lung transplant is akin to ischemic preconditioning, or IPC, which has widely been reported to be protective in several organs. The protection afforded by IPC arises, in part, from activation of KATP channels. Thus, based on the IPC model, use of a KATP agonist would be an obvious choice for reduction of oxidative damage. But although the protective effect of IPC or multiple short episodes (1–3 min) of ischemia followed by reperfusion are known in the central nervous and cardiac systems, there are relatively limited data related to the effects of IPC on lungs. Besides the storage of lungs and the standard EVLP (ex vivo lung perfusion) technique does not mimic an IPC maneuver per se (the ischemic times are considerably longer and range between 1–6 h and the reperfusion too is for longer periods). However, it is possible, as suggested by the author, that having short periods of ischemia, with a period of perfusion between them for EVLP, may reduce oxidative damage. The IPC effect with lung I/R has often been via systemic preconditioning by other remote organ ischemia (such as hind limb or heart)(4, 5). Thus further study of the role of IPC in lung I/R and on the EVLP maneuver is warranted. As suggested by Dr. Mohamed, antagonizing ROS by addition of antioxidants to the lung preservation solution would (by blocking oxidative damage and the inflammation cascade) be a reasonable protective strategy. Thus the hydrogen gas therapy with EVLP may hold promise due to its antioxidant effects but this has been incompletely assessed till date. Alternatively, inhibiting the cascade that leads to ROS production with lung I/R rather than scavenging ROS after they are produced may be a better approach. This is partly because protective antioxidant therapy has had a mixed clinical response so far and because theoretically it is difficult for a ROS scavenger to compete with tissue components for reaction with ROS. Of course, this is not to indicate that the addition of antioxidants either alone or in combination with KATP agonist (s) to the lung perfusate or storage solution would have no additional protective effect. Signaling upon transplant represents the amalgamation of several events. Besides I/R, immunological, inflammatory, and attendant innate immune responses also play a role in oxidative damage and the pathogenesis of graft dysfunction. Understanding these pathways and how they intersect can help identify agents that can attenuate the signaling events that drive this pathogenesis. In this direction, our article highlights how our understanding of the events in the pulmonary endothelial “mechanosignaling” cascade can translate into inclusion of agents in the preservation solution of lung grafts.